The goal of our project is to synthesize a dual CXCR4/CCR5 co-receptor inhibitor to block the entry of HIV into host cells.
In the early phase of the HIV-1 replication cycle, HIV-1 binds to host cells through the CD4 protein present on the host cell surface. To infect the cell, HIV-1 requires further interactions that promote fusion of the viral and cellular membranes. This can occur through binding to the chemokine co-receptors such as CXCR4 and CCR5. We are choosing dual inhibition since under selective pressure of a CCR5 antagonist, CXCR4-using strains have been shown to predominate. Through dual inhibition, we want to account for a possible resistance development that could occur when inhibiting only one of the two co-receptors.
Using a computational screen, a compound predicted to bind to both CCR5 and CXCR4 was identified (Hit 1). We established a reaction scheme to synthesize an analog of this compound (target compound 4) through solid phase peptide synthesis (Scheme 1). We completed the synthesis of compound 4 and we confirmed the addition of the first two amino acids (Fmoc-phenylalanine and Fmoc-proline) through LC-MS and HPLC.
We are currently expecting LC-MS and HPLC results for the rest of the synthesis steps. Before the time of presentation, we plan to use our established methodology to synthesize multiple analogs through varying amino acids and evaluate them for biological activity. The goal of synthesizing analogs is to optimize CXCR4/CCR5 dual inhibition.
